The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy. / Lahrouchi, Najim; Raju, Hariharan; Lodder, Elisabeth M; Papatheodorou, Stathis; Miles, Chris; Ware, James S; Papadakis, Michael; Tadros, Rafik; Cole, Della; Skinner, Jonathan R; Crawford, Jackie; Love, Donald R; Pua, Chee J; Soh, Bee Y; Bhalshankar, Jaydutt D; Govind, Risha; Tfelt-Hansen, Jacob; Winkel, Bo G; van der Werf, Christian; Wijeyeratne, Yanushi D; Mellor, Greg; Till, Janice; Cohen, Marta; Tome-Esteban, Maria; Sharma, Sanjay; Wilde, Arthur A M; Cook, Stuart A; Sheppard, Mary N; Bezzina, Connie R; Behr, Elijah R.
I: European Journal of Human Genetics, Bind 18, 2020, s. 17-22.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy
AU - Lahrouchi, Najim
AU - Raju, Hariharan
AU - Lodder, Elisabeth M
AU - Papatheodorou, Stathis
AU - Miles, Chris
AU - Ware, James S
AU - Papadakis, Michael
AU - Tadros, Rafik
AU - Cole, Della
AU - Skinner, Jonathan R
AU - Crawford, Jackie
AU - Love, Donald R
AU - Pua, Chee J
AU - Soh, Bee Y
AU - Bhalshankar, Jaydutt D
AU - Govind, Risha
AU - Tfelt-Hansen, Jacob
AU - Winkel, Bo G
AU - van der Werf, Christian
AU - Wijeyeratne, Yanushi D
AU - Mellor, Greg
AU - Till, Janice
AU - Cohen, Marta
AU - Tome-Esteban, Maria
AU - Sharma, Sanjay
AU - Wilde, Arthur A M
AU - Cook, Stuart A
AU - Sheppard, Mary N
AU - Bezzina, Connie R
AU - Behr, Elijah R
PY - 2020
Y1 - 2020
N2 - Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.
AB - Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.
U2 - 10.1038/s41431-019-0500-8
DO - 10.1038/s41431-019-0500-8
M3 - Journal article
C2 - 31534214
VL - 18
SP - 17
EP - 22
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
ER -
ID: 227822781